Reactors are used in research and industry to position and maintain gas, liquid and/or solid phases contained therein in contact with each other to effect a reaction. Mixing is often required to obtain the desired amount of contact. Polymerization is one reaction that can be performed. Another reaction is a bioreaction wherein organisms, e.g., cells, are cultured to produce additional cells or a product of the cells. Reactors in which bioreactions are performed are called bioreactors or fermentors. The reactants include the cells and the gas, liquid or solid phases. Bioreactors will be discussed hereinafter, it being understood that similar problems exist with other reactors.
Bioreactors include laboratory (small) scale bioreactors, e.g., stationary shaker and roller bottles, stirred tank, airlift, membrane and rotating drum types. Large scale bioreactors are usually of the stirred tank type, occasionally of the rotating drum type and rarely of the bubble column and airlift type.
Some cell cultures are grown suspended in the liquid phase while others must be attached to a surface (attachment dependent cells) within the bioreactor to be grown. The cells obtain nutrients contained in the gas, liquid or solid phase from direct contact. A uniform and optimal nutrient level throughout the bioreactor is necessary to maximize cell growth and propagation. Adequate mixing contributes to a uniform nutrient level. Other bioreactors have shortcomings that inhibit obtaining a uniform and optimal nutrient level.
Roller bottle, bubble column and airlift bioreactors only provide mixing in one direction and can result in a non-uniform nutrient level. When fresh nutrient-containing gas, solid or liquid phases (medium) are added, they may not be evenly dispersed within the bioreactor or may take an extended time period to be uniformly dispersed. Thus, some of the cells can be exposed to a non-optimal nutrient levels. These problems are exacerbated as the cells grow and propagate which increases the viscosity of the liquid phase and makes mixing and obtaining a uniform and optimal nutrient level more difficult.
Impellers used to effect mixing can damage the cells due to impact of the impeller upon the cells. Damaging of cells is of course contrary to the purpose of the bioreactor. As the cells multiply in suspended culture, they increase the viscosity of the liquid phase which increases the number of cells damaged by the impeller.
Bioreactors that do not permit the gas, liquid and/or solid phases to be removed therefrom or introduced thereto cannot maintain the optimum nutrient level because the cells consume nutrients and change the nutrient level within the bioreactor. Superoptimal levels can be used initially but the optimum levels are only achieved for a short time period and soon suboptimal levels occur. The nutritional requirements of cells change as they go through different stages of growth. A bioreactor that cannot respond to these changes by changing the gas, liquid or solid phases as required cannot maximize cell growth and propagation.
The bioreactor can be opened, spent gas, liquid or solid phases removed therefrom and fresh medium introduced thereto in order to change the nutrient levels. However, opening of the bioreactor is undesirable because sterility must be maintained therein and opening the bioreactor increases the risk that sterility will not be maintained.
Some bioreactors use peristaltic or some other type of pump to introduce and remove gas, liquid or solid phases. When cells are suspended in the liquid phase the pump can damage the cells that pass through the pump. Damaging the cells is contrary to the goal of the bioreactor.
It sometimes is necessary to test the contents of the bioreactor to determine the developmental stage of the cells, the nutritional level, gas level or the like within the bioreactor. Many bioreactors, e.g., roller bottles, do not provide a mechanism for sampling while the bioreactor is operating. Roller drums may provide for sampling but not without an external pump which, as discussed above, can damage the cells.
The surface area of many bioreactors is limited which limits the number of cells that can be attached thereto. Often, a large number of roller bottles are used to culture attachment dependent cells. The number of cells per roller bottle is limited by the surface area of the interior of the roller bottle, not by its volume.
A reactor that does not exhibit the aforementioned shortcoming of the existing reactors is highly desirable.